Cancer appears to be, in many ways, a disease of the cell cycle. The molecular components of the cellular machinery that drives the cell cycle are being uncovered in rapid succession. Whether a cell enters the cycle and proceeds to cell division depends largely on the input it receives from growth factors and growth inhibitors in the extracellular milieu. The secreted polypeptide, Transforming Growth Factor-beta (TGF-beta), is the most potent known inhibitor of cell division of normal epithelial cell and induces the accumulation of extracellular matrix. These dual biological effects of TGFbeta1 are mediated by a complex of two interacting and interdependent receptor serin/threonine kinases, type I (TbetaR-I) and type II (TbetaR-II). In spite of the voluminous literature that supports the notion that escape from TGFbeta-mediated growth control plays and important part in malignant transformation, there is virtually no information on the molecular status of TGFbeta receptors in cancer in general and of squamous cell carcinomas of the upper aero-digestive tract (i.e. head-&- neck, esophagus and lung) in particular. The central hypothesis is that genetic alterations in this TGFbeta receptor system play an important role in squamous epithelial cell transformation by fundamentally altering the ways cells respond to TGFbeta1's signals. Dr. Reiss has identified several different SqCC cell lines in which the TbetaR-II gene carries point mutations, which result in amino acid substitution at highly conserved sites within the cytoplasmic domain of the protein. These mutations appear to alter the secondary structure, kinase activity and interactions of the type II receptor with TbetaR-I. This the first clear evidence that TbetaR mutants occur naturally in human cancer cells and provides strong support for my hypothesis. These observations raise the questions (1) how these mutation affect the biochemical, functional and biological properties of the TGFbeta receptor system; (2) what role they play in tumor development; (3) at which stage of tumor development these mutations are acquired in vivo and whether or not they carry any prognostic significance. These are the questions we plan to address during the next five years. In the longer term, these studies should lead to the development of molecular and/or pharmacological tools to correct the dysfunction of the TGFbeta receptor system in human cancers. As the TGFbeta system appears to play an important role in many different types of cancer, the significance of our findings is likely to extend far beyond that of aero-digestive tract cancer.